This invention relates generally to human and veterinary medical devices, and, particularly, to implantable medical devices with or without incorporating drugs or bioactive agents and, more particularly, to an implantable device including silver with or without incorporating drugs or bioactive agents.
It has become common to treat a variety of medical conditions by introducing an implantable medical device partly or completely into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. For example, many treatments of the vascular system entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like. However, when such a device is introduced into and manipulated through the vascular system, the blood vessel walls can be disturbed or injured. Clot formation or thrombosis often results at the injured site, causing stenosis or occlusion of the blood vessel. Moreover, if the medical device is left within the patient for an extended period of time, thrombus often forms on the device itself, again causing stenosis or occlusion. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke. Thus, the use of such a medical device can entail the risk of precisely the problems that its use was intended to ameliorate.
Another way in which blood vessels undergo stenosis is through disease. Probably the most common disease causing stenosis of blood vessels is atherosclerosis. Atherosclerosis is a condition which commonly affects the coronary arteries, the aorta, the iliofemoral arteries and the carotid arteries. Atherosclerotic plaques of lipids, fibroblasts, and fibrin proliferate and cause obstruction of an artery or arteries. As the obstruction increases, a critical level of stenosis is reached, to the point where the flow of blood past the obstruction is insufficient to meet the metabolic needs of the tissue distal to (downstream of) the obstruction. The result is ischemia.
Many medical devices and therapeutic methods are known for the treatment of atherosclerotic disease. One particularly useful therapy for certain atherosclerotic lesions is percutaneous transluminal angioplasty (PTA). During PTA, a balloon-tipped catheter is inserted in a patient""s artery, the balloon being deflated. The tip of the catheter is advanced to the site of the atherosclerotic plaque to be dilated. The balloon is placed within or across the stenotic segment of the artery, and then inflated. Inflation of the balloon xe2x80x9ccracksxe2x80x9d the atherosclerotic plaque and expands the vessel, thereby relieving the stenosis, at least in part.
While PTA presently enjoys wide use, it suffers from two major problems. First, the blood vessel may suffer acute occlusion immediately after or within the initial hours after the dilation procedure. Such occlusion is referred to as xe2x80x9cabrupt closure.xe2x80x9d Abrupt closure occurs in perhaps five percent or so of the cases in which PTA is employed, and can result in myocardial infarction and death if blood flow is not restored promptly. The primary mechanisms of abrupt closures are believed to be elastic recoil, arterial dissection and/or thrombosis. It has been postulated that the delivery of an appropriate agent (such as an antithrombic) directly into the arterial wall at the time of angioplasty could reduce the incidence of thrombotic acute closure, but the results of attempts to do so have been mixed.
A second major problem encountered in PTA is the re-narrowing of an artery after an initially successful angioplasty. This re-narrowing is referred to as xe2x80x9crestenosisxe2x80x9d and typically occurs within the first six months after angioplasty. Restenosis is believed to arise through the proliferation and migration of cellular components from the arterial wall, as well as through geometric changes in the arterial wall referred to as xe2x80x9cremodeling.xe2x80x9d It has similarly been postulated that the delivery of appropriate agents directly into the arterial wall could interrupt the cellular and/or remodeling events leading to restenosis. However, like the attempts to prevent thrombotic acute closure, the results of attempts to prevent restenosis in this manner have been mixed.
Non-atherosclerotic vascular stenosis may also be treated by PTA. For example, Takayasu arteritis or neurofibromatosis may cause stenosis by fibrotic thickening of the arterial wall. Restenosis of these lesions occurs at a high rate following angioplasty, however, due to the fibrotic nature of the diseases. Medical therapies to treat or obviate them have been similarly disappointing.
A device such as an intravascular stent can be a useful adjunct to PTA, particularly in the case of either acute or threatened closure after angioplasty. The stent is placed in the dilated segment of the artery to mechanically prevent abrupt closure and restenosis. Unfortunately, even when the implantation of the stent is accompanied by aggressive and precise antiplatelet and anticoagulation therapy (typically by systemic administration), the incidence of thrombotic vessel closure or other thrombotic complication remains significant, and the prevention of restenosis is not as successful as desired. Furthermore, an undesirable side effect of the systemic antiplatelet and anticoagulation therapy is an increased incidence of bleeding complications, most often at the percutaneous entry site.
Other conditions and diseases are treatable with stents, catheters, cannulae and other devices inserted into the esophagus, trachea, colon, biliary tract, urinary tract and other locations in the body, or with orthopedic devices, implants, or replacements. It would be desirable to develop devices and methods for reliably delivering suitable agents, drugs or bioactive materials directly into a body portion during or following a medical procedure, so as to treat or prevent such conditions and diseases, for example, to prevent abrupt closure and/or restenosis of a body portion such as a passage, lumen or blood vessel. As a particular example, it would be desirable to have devices and methods which can deliver an antithrombic or other medication to the region of a blood vessel which has been treated by PTA, or by another interventional technique such as atherectomy, laser ablation, or the like. It would also be desirable that such devices would deliver their agents over both the short term (that is, the initial hours and days after treatment) and the long term (the weeks and months after treatment). It would also be desirable to provide precise control over the delivery rate for the agents, drugs or bioactive materials, and to limit systemic exposure to them. This would be particularly advantageous in therapies involving the delivery of a chemotherapeutic agent to a particular organ or site through an intravenous catheter (which itself has the advantage of reducing the amount of agent needed for successful treatment), by preventing stenosis both along the catheter and at the catheter tip. A wide variety of other therapies could be similarly improved. Of course, it would also be desirable to avoid degradation of the agent, drug or bioactive material during its incorporation on or into any such device.
When an angioplasty is performed in a vessel, the inner layers of the vessel can be split or torn as the vessel is expanded. Stents are then frequently employed to keep the vessel open after angioplasty and to hold the torn or damaged tissue out of the blood stream. The result is usually very good in the short term; however, after six months to one year after the initial procedure, the vessels frequently become narrow again. Studies into the reason for the restenosis in these cases have shown that the restenosis is primarily due to the proliferation of fibroblasts resulting from the healing process that takes place in the vessel after the angioplasty. This proliferation of fibroblasts results in the formation of new tissue commonly known as smooth muscle cell proliferation to create a new restriction to blood flow in the vessel.
Other problems experienced with the use of catheters, particularly catheters designed for urinary tract infections present a significant risk in patients with an in dwelling catheter. Although most of such infections are asymptomatic, they are sometimes serious and can result in prolonging the length of stay and increasing the cost of hospital care. Bacteria are believed to gain access to the catheterized bladder either by migration from the collection bag and/or catheter or by ascending the periurethral space outside the catheter. It has been found that by coating catheters with silver or silver oxide reduced the incidence of catheter associated bacteriuria. Silver is known to possess antibacterial properties and is used topically either as a metal or as silver salts. It is not absorbed to any great extent and the main problem associated with the metal is argyria, a general grey discoloration.
The foregoing problems are solved and a technical advance is achieved in an illustrative silver vascular stent or other silver implantable medical device that advantageously reduces if not minimizes the proliferation of fibroblasts and the incidents of restenosis in stented vessels. The silver containing vascular stents can be balloon expandable, self-expanding, or any combination thereof. The balloon expandable silver stent can be deployed at the same time an angioplasty procedure is performed, thus advantageously requiring only one medical procedure. A solid silver vascular stent lends itself well to use in balloon expandable stents because of the malleable nature of the silver. The balloon expandable silver stent can also be made from a base material with good mechanical properties for stenting that is coated with silver by any one of a number of processes. These processes include electroplating, electrostatic, electrolytic ion beam deposition or implantation, sputtering, vacuum deposition or other known application processes over base stent metals such as stainless steel, tantalum, nickel titanium alloys such as nitinol, polymer or copolymer plastics, copper, zinc, platinum, silver or gold, etc. The silver coating (which is used generically to indicate the application or inclusion in silver in any of the above-referenced application processes) can be applied directly to the base material or to an intermediate coating such as parylene or an other metallic coating, e.g. Ti and Pd. The vascular stent or implantable medical device can also be made entirely of silver. Experience with central venous access catheters that have a silver coating for anti-sepsis has shown that a coating of silver with only a 3,000 angstroms thickness is adequate to be effective.
Silver can be alloyed with other materials both in the base stent or device material and/or in the coating. As a preferred example, the addition of a small amount of copper to silver will increase its tensile strength. Pure silver has a maximum tensile strength of about 56 Kpsi. 85% silver and 15% copper has a maximum tensile strength of about 91 Kpsi, whereas a mixture of 50% silver with 50% copper can have a maximum tensile strength of over 200 Kpsi.
The silver can be used in conjunction with other drugs or medicaments on the stent such as Heparin, Taxol, Dexamethosone along with others here after described to further enhance the stents or medical device or implantable medical devices"" antithrombogenic or antiproliferative ability. Both the balloon expandable stent as well as the self-expanding stent can be assembled and/or completely coated or tinned with a silver barring solder (for example, 70% silver, 15% copper, 15% zinc) which can provide or supplement the antiproliferative action.
Furthermore and advantageously, silver can be used alone, as a coating, in combination with other carrier, drug or medicament materials, as one of several other layers of materials, and with base materials that are used to improve the adhesion of silver to any other carrier, drug, medicament or base material. Advantageously, silver can be ion beam bombarded or implanted to provide a specific surface energy density in the preferred range of 20 to 30 dynes per centimeter. In this particular range, not only is the antiproliferative effect of the stent or device enhanced but the outer surface of the stent or device is resistant to the formation of thrombus, fungus, bacteria, and encrustations thereon. Silver coatings, implantations, impregnations or dispersions having a thickness in the range of 3,000 angstroms to 0.005 inches are contemplated dependent on the thickness of the base material or intermediate layers thereon. Stents or other implantable medical devices using a base material with a silver coating deposited directly thereon is one example of a coating configuration. Another configuration of the stent is to include a base material with a coating of a carrier or dispersant material such as parylene positioned thereon or therein along with a coating, deposition, impregnation, or implantation and the like thereon is also contemplated. Another configuration of the silver stent can include a base material with alternating layers of a carrier material, silver, drug or medicament is also contemplated. Various recesses or cavities included in the surface or made part of the stent or implantable medical device are also contemplated and included with the silver device.
The foregoing problems are solved and a technical advance is achieved in an illustrative vascular stent or other implantable medical device that provides a controlled release of an agent, drug or bioactive material into the vascular or other system, or other location in the body, in which a stent or other device is positioned. Applicants have discovered that the degradation of an agent, a drug or a bioactive material applied to such a device can be avoided by covering the agent, drug or bioactive material with a porous layer of a biocompatible polymer that is applied without the use of solvents, catalysts, heat or other chemicals or techniques, which would otherwise be likely to degrade or damage the agent, drug or material. Those biocompatible polymers may be applied preferably by vapor deposition or plasma deposition, and may polymerize and cure merely upon condensation from the vapor phase, or may be photolytically polymerizable and are expected to be useful for this purpose. However, it should be recognized that other coating techniques may also be employed.
In a first aspect, then, the present invention is directed in its simplest form to an implantable medical device comprising a structure adapted for introduction into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location in a human or veterinary patient, the structure being composed of a base material; at least one layer of a bioactive material posited on one surface of the structure or posited in wells, holes, grooves, slots and the like contained in the structure; and at least one porous layer posited over the bioactive material layer and the bioactive-material-free surface, the porous layer being composed of a polymer and having a thickness adequate to provide a controlled release of the bioactive material.
Preferably, when the device is intended for use in the vascular system, the bioactive material in the at least one layer is heparin or another antiplatelet or antithrombotic agent, or dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, or another dexamethasone derivative or anti-inflammatory steroid. Furthermore, a wide range of other bioactive materials can be employed, including, but not limited to, the following categories of agents: thrombolytics, vasodilators, antihypertensive agents, antimicrobials or antibiotics, antimitotics, antiproliferatives, antisecretory agents, non-steroidal anti-inflammatory drugs, immunosuppressive agents, growth factors and growth factor antagonists, antitumor and/or chemotherapeutic agents, antipolymerases, antiviral agents, photodynamic therapy agents, antibody targeted therapy agents, prodrugs, sex hormones, free radical scavengers, antioxidants, biologic agents, radiotherapeutic agents, radiopaque agents and radiolabeled agents. The major restriction is that the bioactive material must be able to withstand the coating techniques, for example, the vacuum employed during vapor deposition or plasma deposition of the at least one porous layer. In other words, the bioactive material must have a relatively low vapor pressure at the deposition temperature, typically, near or at room temperature.
The at least one porous layer is preferably composed of a polyamide, parylene or a parylene derivative applied by catalyst-free vapor deposition and is conveniently about 5,000 to 250,000 xc3x85 thick, which is adequate to provide a controlled release of the bioactive material. xe2x80x9cParylenexe2x80x9d is both a generic name for a known group of polymers based on p-xylylene and made by vapor phase polymerization, and a name for the unsubstituted form of the polymer; the latter usage is employed herein. More particularly, parylene or a parylene derivative is created by first heating p-xylene or a suitable derivative at an appropriate temperature (for example, at about 950xc2x0 C.) to produce the cyclic dimer di-p-xylylene (or a derivative thereof). The resultant solid can be separated in pure form, and then cracked and pyrolyzed at an appropriate temperature (for example, at about 680xc2x0 C.) to produce a monomer vapor of p-xylylene (or derivative); the monomer vapor is cooled to a suitable temperature (for example, below 50xc2x0 C.) and allowed to condense on the desired object, for example, on the at least one layer of bioactive material. The resultant polymer has the repeating structure "Parenopenst"CH2C6H4CH2"Parenclosest"n, with n equal to about 5,000, and a molecular weight in the range of 500,000.
As indicated, parylene and parylene derivative coatings applicable by vapor deposition are known for a variety of biomedical uses, and are commercially available from or through a variety of sources, including Specialty Coating Systems (100 Deposition Drive, Clear Lake, Wis. 54005), Para Tech Coating, Inc. (35 Argonaut, Aliso Viejo, Calif. 92656) and Advanced Surface Technology, Inc. (9 Linnel Circle, Billerica, Mass. 01821-3902).
The at least one porous layer can alternatively be applied by plasma deposition. Plasma is an ionized gas maintained under vacuum and excited by electrical energy, typically in the radiofrequency range. Because the gas is maintained under vacuum, the plasma deposition process occurs at or near room temperature. Plasma can be used to deposit polymers such as poly(ethylene oxide), polyfethylene glycol), and poly(propylene oxide), as well as polymers of silicone, methane, tetrafluoroethylene (including TEFLON brand polymers), tetramethyldisiloxane, and others.
While the foregoing represents some preferred embodiments of the present invention, other polymer systems may also be employed, e.g., polymers derived from photopolymerizeable monomers. Also, other coating techniques may be utilized, e.g., dipping, spraying, and the like.
The device may include two or more layers of different bioactive materials atop the structure. However, for the purposes of the present invention, the same bioactive material will generally not be posited on the different surfaces of the device within the same layer. In other words, each surface of the device structure will carry a different bioactive material or materials except where the bioactive material is the innermost or outermost layer, e.g. heparin may form the innermost layer or the outermost layer or both. These additional layers may be placed directly atop one another or can be separated by additional porous polymer layers between each of them. Additionally, the layers of bioactive materials can comprise a mixture of different bioactive materials. The porous layers are also preferably composed of parylene or a parylene derivative. Advantageously, the two or more bioactive materials can have different solubilities, and the layer containing the less soluble bioactive material (for example, dexamethasone) is preferably posited above the layer containing the more soluble bioactive material (for example, heparin). Unexpectedly, this has been found to increase the in vitro release rate of some relatively less soluble materials such as dexamethasone, while simultaneously decreasing the release rate of some relatively more soluble materials such as heparin.
While the structure included in the device may be configured in a variety of ways, the structure is preferably configured as a vascular stent composed of a biocompatible metal such as stainless steel, nickel, silver, platinum, gold, titanium, tantalum, iridium, tungsten, Nitinol, Inconel, or the like. An additional substantially nonporous coating layer of parylene or a parylene derivative or other biocompatible polymer of about 50,000 to 500,000 xc3x85 thick may be posited directly atop the vascular stent, beneath the at least one layer of bioactive material. The additional coating layer can merely be relatively less porous than the at least one porous layer, but preferably is substantially nonporous, that is, sufficiently nonporous to render the stent essentially impervious to blood during normal circumstances of use.
In a second aspect, the present invention is directed to a method of making an implantable medical device of the type disclosed above, in which the method comprises the steps of: depositing at least one layer of a bioactive material on one surface of the structure; and depositing at least one porous layer over the at least one bioactive material layer and the bioactive-material-free surface, the at least one porous layer being composed of a polymer and being of a thickness adequate to provide a controlled release of the bioactive material. Conveniently and in a preferred embodiment, the at least one porous layer is polymerized from a monomer vapor which is free of any solvent or polymerization catalyst, and cures by itself upon condensation, without any additional heating or curing aid (for example, visible or ultraviolet light). The at least one layer of the bioactive material may be deposited on the one surface of the structure by any convenient method such as dipping, rolling, brushing, spraying, electrostatic deposition, or the like.
Lastly, in a third aspect, the present invention is directed to an improvement in a method of medically treating a human or veterinary patient by the step of inserting an implantable medical device into the body of the patient, the device comprising a structure adapted for introduction into an applicable system of or location in the patient, and the structure being composed of a base material, in which the procedure comprises the preliminary steps of: depositing at least one layer of a bioactive material on one surface of the structure; and depositing at least one porous layer over the at least one bioactive material layer and the bioactive-material-free surface, the at least one porous layer being composed of a polymer having a thickness adequate to provide a controlled release of the bioactive material.
The device and methods of the present invention are useful in a wide variety of locations within a human or veterinary patient, such as in the esophagus, trachea, colon, biliary tract, urinary tract and vascular system, as well as for subdural and orthopedic devices, implants or replacements.
They are particularly advantageous for reliably delivering suitable bioactive materials during or following an intravascular procedure, and find particular use in preventing abrupt closure and/or restenosis of a blood vessel. More particularly, they permit, for example, the delivery of an antithrombotic, an antiplatelet, an anti-inflammatory steroid, or another medication to the region of a blood vessel which has been opened by PTA. Likewise, it allows for the delivery of one bioactive material to, for example, the lumen of a blood vessel and another bioactive material to the vessel wall. The use of a porous polymer layer permits the release rate of a bioactive material to be carefully controlled over both the short and long terms.
These and other aspects of the present invention will be appreciated by those skilled in the art upon the reading and understanding of the specification.